Malaria and other parasitic diseases are the greatest health problem currently facing the developing world, and P. falciparum malaria is a particularly severe problem in sub-Saharan Africa. Drug development is a necessary approach to reducing the worldwide impact of malaria, because it is the only approach that will benefit the millions of people currently afflicted with this disease. Natural products are a known, excellent source of antimalarial compounds. Two of the most effective antimalarial drugs (quinine and artemisinin) are natural products, and many synthetic antimalarial drugs are analogs of these two natural products. In addition to the use of isolated natural products as antimalarial agents, many plants are used ethno medically for the treatment of malaria. The development of new antimalarial natural products is however handicapped by a lack of understanding of their mechanism of action. This research will combine the antimalarial expertise of two research groups at Virginia Tech (VT) with the natural product resources of the Natural Products Discovery Institute (NPDI) in a collaborative program to tap into the enormous potential of natural products to serve as antimalarial agents. The NPDI maintains a repository of over 22,000 samples prepared from a total of approximately 7500 plant specimens. The antimalarial activity of a set of extracts from twelve plants in this collection with an ethno medical history of use as antimalarial agents has been validated at VT, and these extracts will be supplied by NPDI for isolation of novel antimalarial compounds from plants used in complementary and alternative medicine (CAM). In addition, all 22,000 extracts from the NPDI will be assayed for antimalarial activity by Dr. Belen Cassera at VT using a standard antimalarial bioassay to identify active extracts. Extracts which pass rigorous selection criteria will then be fractionated by Dr. David Kingston at VT, who will isolate and determine the structures of the active compounds from both the ethno medical extracts and active extracts found by screening the entire NPDI collection. Isolated compounds will be evaluated for stage specific activity (asexual intraerythrocytic stages, gametocytocidal, and liver stages), as well as cytocidal and anti-apicoplast activity to identify lead inhibitors wih different modes of action. The three most promising leads will then be selected to elucidate their mode of action and potential molecular target(s) using proteomics, metabolomics and transcriptomics approaches, with the ultimate goal of finding a novel antimalarial agent with a new mechanism of action. Synthetic chemistry will provide analogs of these lead compounds for future drug development.